Inflammation damages the joints of rheumatoid arthritis (RA) patients. They experience pain, loss of motion, physical disability and a shortened lifespan. Despite estimates suggesting Mexican Americans (MA) may be more susceptible to RA than other major U.S. ethnic groups, little is known about the clinical expression or outcome in RA in MA. Our goals are to identify optimal points for intervention to retard disablement in RA, and to understand the mechanisms of ethnic disparities. Toward these goals, we developed a novel biopsychosocial model of disability in RA, which guided our study of a multiethnic cohort of 779 RA patients. During the initial funding period from 1999 to 2005, we followed the cohort for 3,967 patient-years. Key findings from the initial period that we aim to study further include: First, a significant ethnic disparity in the clinical expression of RA, MA having more severe manifestations at every stage of the disablement process; and second, extreme variation among the patients in the accrual of joint damage. Our Specific Aims are: 1) To identify gene variants (single nucleotide polymorphisms, or SNPs), associated with the joint damage phenotype in RA, and to examine their downstream influence on the disablement process; 2) To examine the extent to which ethnic variation in the disablement process in RA is explained by genetic and environmental factors; and 3) To examine the influence of ethnicity, genetic and environmental factors on survival in RA. We will study MA and non-Hispanic White (NHW) members of the original RA cohort (n=655) and will recruit additional patients for a combined sample size of 500 MA and 500 NHW RA patients. We will follow patients longitudinally to evaluate the process of disablement, and survival. We will study 25 carefully selected candidate genes found previously to be associated with RA susceptibility and/or severity. In each gene, we will genotype an average of 20 SNPs, selected to capture the largest amount of regional genetic information, or for their potential to alter gene function. We will use Bayesian Quantitative Trait Nucleotide analysis (BQTN) to identify SNPs associated with joint damage. This research will advance current understanding of the genotype-phenotype relationship in RA, and of how genes and the environment contribute to ethnic disparities in the disablement process. SNPs associated with RA damage may be useful for risk stratification of patients, and may contribute to the discovery of novel targets for RA treatments. [unreadable] [unreadable] [unreadable] [unreadable]